Pyran analogs of trans-4,5-didehydro-PGI compounds

ABSTRACT

The present invention provides pyran analogs of trans-4,5-didehydro-PGI compounds, which are useful pharmacological agents. The compounds of the present invention exhibit prostacyclin-like pharmacological properties.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of Ser. No. 821,542, filed Aug. 3, 1977, now pending issuance as a U.S. patent.

The present invention relates to pyran analogs of trans-4,5-didehydro-PGI₁ compounds, the essential material constituting a disclosure thereof being hereby incorporated from U.S. Pat. No. 4,109,082, issued Aug. 22, 1978. 

I claim:
 1. A prostacyclin analog of the formula ##STR1## wherein Z₂ is ##STR2## wherein one of p and q is the integer one and the other is the integer zero;Wherein Z₁ is(1) --(CH₂)_(g) --CH₂ --CH₂ --, or (2) --(CH₂)_(g) --CH₂ --CF₂ --, wherein g is the integer zero, one, or 2; Wherein R₈ is hydrogen, hydroxy, or hydroxymethyl; Wherein Y₁ is(1) trans--CH═CH--, (2) cis--CH═CH--, or (3) --CH₂ CH₂ --, wherein M₁ is ##STR3## wherein R₅ is hydrogen or alkyl with one to 4 carbon atoms, inclusive, Wherein L₁ is ##STR4## or a mixture of ##STR5## wherein R₃ and R₄ are hydrogen, methyl, or fluoro, being the same or different, with the proviso that one of R₃ and R₄ is fluoro only when the other is hydrogen or fluoro; Wherein X₁ is(1) --COOR₁ wherein R₁ is hydrogen; alkyl of one to 12 carbon atoms, inclusive; cycloalkyl of 3 to 10 carbon atoms, inclusive; aralkyl of 7 to 12 carbon atoms, inclusive; phenyl; phenyl substituted with one, two or three chloro or alkyl of one to 3 carbon atoms; phenyl substituted in the para position by ##STR6## wherein R₂₅ is methyl, phenyl, acetamidophenyl, benzamidophenyl, or --NH₂ ; R₂₆ is methyl, phenyl, --NH₂, or methoxy; and R₂₇ is hydrogen or acetamido; inclusive, phenacyl, i.e., ##STR7## phenacyl substituted in the para position by chloro, bromo, phenyl, or benzamido; or a pharmacologically acceptable cation; (2) --CH₂ OH; (3) --ch₂ nl₂ l₃ wherein L₂ and L₃ are hydrogen or alkyl of one to 4 carbon atoms, inclusive; or (4) --COL₄, wherein L₄ is(a) amino of the formula --NR₂₁ R₂₂, wherein R₂₁ and R₂₂ are hydrogen; alkyl of one to 12 carbon atoms, inclusive; cycloalkyl of 3 to 10 carbon atoms, inclusive; aralkyl of 7 to 12 carbon atoms, inclusive; phenyl; phenyl substituted with one, 2, or 3 chloro, alkyl of one to 3 carbon atoms, inclusive; hydroxy, carboxy, alkoxycarbonyl of one to 4 carbon atoms, inclusive, or nitro; carboxyalkyl of one to 4 carbon atoms, inclusive; carbamoylalkyl of one to 4 carbon atoms, inclusive; cyanoalkyl of one to 4 carbon atoms, inclusive; acetylalkyl of one to 4 carbon atoms, inclusive; benzoylalkyl of one to 4 carbon atoms, inclusive; benzoylalkyl substituted by one, 2, or 3 chloro, alkyl of one to 3 carbon atoms, inclusive; hydroxy, alkoxy of one to 3 carbon atoms, inclusive; carboxy, alkoxycarbonyl of one to 4 carbon atoms, inclusive; or nitro; pyridyl; pyridyl substituted by one, 2, or 3 chloro, alkyl of one to 3 carbon atoms, inclusive; or alkoxy of one to 3 carbon atoms, inclusive; pyridylalkyl of one to 4 carbon atoms, inclusive; pyridylalkyl substituted by one, 2, or 3 chloro, alkyl of one to 3 carbon atoms inclusive; hydroxy, alkoxy of one to 3 carbon atoms, inclusive; hydroxyalkyl of one to 4 carbon atoms, inclusive; dihydroxyalkyl of one to 4 carbon atoms, and trihydroxyalkyl of one to 4 carbon atoms; with the further proviso that not more than one of R₂₁ and R₂₂ is other than hydrogen or alkyl; (b) cycloamino selected from the group consisting of ##STR8## wherein R₂₁ and R₂₂ are as defined above; (c) carbonylamino of the formula --NR₂₃ COR₂₁, wherein R₂₃ is hydrogen or alkyl of one to 4 carbon atoms and R₂₁ is as defined above; (d) sulphonylamino of the formula --NR₂₃ SO₂ R₂₁, wherein R₂₁ and R₂₃ are as defined above; or (e) hydrazino of the formula --NR₂₃ R₂₄, wherein R₂₃ is as defined above and R₂₄ is amino of the formula --NR₂₁ R₂₂, as defined above, or cycloamino, as defined above; wherein R₇ is ##STR9## wherein m is the integer one to 5, inclusive, h is the integer zero to 3, inclusive; s is the integer zero, one, 2, or 3, and T is chloro, fluoro, trifluoromethyl, alkyl of one to 3 carbon atoms, inclusive, or alkoxy of one to 3 carbon atoms, inclusive, with the proviso that not more than two T's are other than alkyl; and the pharmacologically acceptable acid addition salts thereof when X₁ is --CH₂ NL₂ L₃.
 2. A prostacyclin analog according to claim 1, wherein R₈ is hydroxymethyl.
 3. 11-Deoxy-11.alpha.-hydroxymethyl-7a-homo-trans-4,5-didehydro-6α-PGI₁, a prostacyclin analog according to claim
 2. 4. A prostacyclin analog according to claim 1, wherein R₈ is hydrogen.
 5. 11-Deoxy-7a-homo-trans-4,5-didehydro-6α-PGI₁, a prostacyclin analog according to claim
 4. 6. A prostacyclin analog according to claim 1, wherein R₈ is hydroxy.
 7. A prostacyclin analog according to claim 6, wherein p is one.
 8. (6R)-trans-4,5-Didehydro-9-deoxy-6,9α-epoxymethylene-PGF₁, a prostacyclin analog according to claim
 7. 9. A prostacyclin analog according to claim 6, wherein q is one.
 10. A prostacyclin analog according to claim 6, wherein Z₂ is a mixture of ##STR10##
 11. 7a-Homo-(6RS)-trans-4,5-didehydro-PGI₁, a prostacyclin analog according to claim
 10. 12. A prostacyclin analog according to claim 6, wherein Z₂ is ##STR11##
 13. 7a-Homo-trans-4,5-didehydro-6α-PGI₁, a prostacyclin analog according to claim
 12. 14. 7a-Homo-15-methyl-trans-4,5-didehydro-6α-PGI₁, a prostacyclin analog according to claim
 12. 15. 7a-Homo-16,16-dimethyl-trans-4,5-didehydro-6α-PGI₁, a prostacyclin analog according to claim
 12. 16. 7a-Homo-2,2-difluoro-15-methyl-trans-4,5-didehydro-6α-PGI₁, a prostacyclin analog according to claim
 12. 17. A prostacyclin analog according to claim 6, wherein Z₂ is ##STR12##
 18. A prostacyclin analog according to claim 17, wherein Y₁ is cis--CH═CH--.
 19. 7a-Homo-cis-13-trans-4,5-didehydro-6β-PGI₁, a prostacyclin analog according to claim
 18. 20. A prostacyclin analog according to claim 17, wherein Y₁ is --CH₂ CH₂ --.
 21. 7a-Homo-13,14-dihydro-trans-4,5-didehydro-6β-PGI₁, a prostacyclin analog according to claim
 20. 22. 7a-Homo-13,14-dihydro-15-methyl-trans-4,5-didehydro-6β-PGI₁, a prostacyclin analog according to claim
 20. 23. 7a-Homo-13,14-dihydro-16,16-dimethyl-trans-4,5-didehydro-6β-PGI₁, a prostacyclin analog according to claim
 20. 24.7a-Homo-13,14-dihydro-2,2-difluoro-15-methyl-trans-4,5-didehydro-6β-PGI₁, a prostacyclin analog according to claim
 20. 25. 7a-Homo-13,14-dihydro-2,2,16,16-tetrafluoro-trans-4,5-didehydro-6β-PGI₁, a prostacyclin analog according to claim
 20. 26. A prostacyclin analog according to claim 17, wherein Y₁ is trans--CH═CH--.
 27. A prostacyclin analog according to claim 26, wherein Z₁ is --(CH₂)_(g) --CH₂ --CF₂ --.
 28. 7a-Homo-2,2-difluoro-15-methyl-trans-4,5-didehydro-6β-PGI₁, a prostacyclin analog according to claim
 27. 29. 7a-Homo-2,2-difluoro-16,16-dimethyl-trans-4,5-didehydro-6β-PGI₁, a prostacyclin analog according to claim
 27. 30. 7a-Homo-2,2,16,16-tetrafluoro-trans-4,5-didehydro-6β-PGI₁, a prostacyclin analog according to claim
 27. 31. A prostacyclin analog according to claim 26, wherein Z₁ is --(CH₂)_(g) --CH₂ --CH₂ --.
 32. A prostacyclin analog according to claim 31, wherein g is zero.
 33. A prostacyclin analog according to claim 32, wherein R₇ is ##STR13##
 34. 7a-Homo-17-phenyl-18,19,20-trinor-trans-4,5-didehydro-6β-PGI₁, a prostacyclin analog according to claim
 33. 35. A prostacyclin analog according to claim 32, wherein R₇ is ##STR14##
 36. 7a-Homo-16-phenoxy-17,18,19,20-tetranor-trans-4,5-didehydro-6β-PGI.sub.1, a prostacyclin analog according to claim
 35. 37. A prostacyclin analog according to claim 32, wherein R₇ is --(CH₂)_(m) --CH₃ --.
 38. A prostacyclin analog according to claim 37, wherein m is
 3. 39. A prostacyclin analog according to claim 38, wherein X₁ is --COL₄.
 40. 7a-Homo-trans-4,5-didehydro-6β-PGI₁, amide, a prostacyclin analog according to claim
 39. 41. A prostacyclin analog according to claim 39, wherein X₁ is --CH₂ OH.
 42. 7a-Homo-2-decarboxy-2-hydroxymethyl-trans-4,5-didehydro-6β-PGI₁, a prostacyclin analog according to claim
 41. 43. A prostacyclin analog according to claim 38, wherein X₁ is --COOR₁.
 44. A prostacyclin analog according to claim 43, wherein R₅ is methyl.
 45. 7a-Homo-15-methyl-trans-4,5-didehydro-6β-PGI₁, a prostacyclin analog according to claim
 44. 46. A prostacyclin analog according to claim 43, wherein R₅ is hydrogen.
 47. A prostacyclin analog according to claim 46, wherein at least one of R₃ and R₄ is fluoro.
 48. 7a-Homo-16,16-difluoro-trans-4,5-didehydro-6β-PGI₁, a prostacyclin analog according to claim
 47. 49. A prostacyclin analog according to claim 46, wherein at least one of R₃ and R₄ is methyl.
 50. 7a-Homo-16,16-dimethyl-trans-4,5-didehydro-6β-PGI₁, a prostacyclin analog according to claim
 49. 51. A prostacyclin analog according to claim 46, wherein R₃ and R₄ are both hydrogen.
 52. 7a-Homo-trans-4,5-didehydro-6β-PGI₁, methyl ester, a prostacyclin analog according to claim
 51. 53. 7a-Homo-trans-4,5-didehydro-6β-PGI₁, tris(hydroxymethyl)amino methane salt, a prostacyclin analog according to claim
 51. 54. 7a-Homo-trans-4,5-didehydro-6β-PGI₁, adamantanamine salt, a prostacyclin analog according to claim
 51. 55. 7a-Homo-trans-4,5-didehydro-6β-PGI₁, a prostacyclin analog according to claim
 51. 